Cardiomuscular Biomarkers in the Diagnosis and Prognostication of Immune Checkpoint Inhibitor Myocarditis.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are approved for multiple cancers but can result in ICI-associated myocarditis, an infrequent but life-threatening condition. Elevations in cardiac biomarkers, specifically troponin-I (cTnI), troponin-T (cTnT), and creatine kinase (CK), are used for diagnosis. However, the association between temporal elevations of these biomarkers with disease trajectory and outcomes has not been established. METHODS: We analyzed the diagnostic accuracy and prognostic performances of cTnI, cTnT, and CK in patients with ICI myocarditis (n=60) through 1-year follow-up in 2 cardio-oncology units (APHP Sorbonne, Paris, France and Heidelberg, Germany). A total of 1751 (1 cTnT assay type), 920 (4 cTnI assay types), and 1191 CK sampling time points were available. Major adverse cardiomyotoxic events (MACE) were defined as heart failure, ventricular arrhythmia, atrioventricular or sinus block requiring pacemaker, respiratory muscle failure requiring mechanical ventilation, and sudden cardiac death. Diagnostic performance of cTnI and cTnT was also assessed in an international ICI myocarditis registry. RESULTS: Within 72 hours of admission, cTnT, cTnI, and CK were increased compared with upper reference limits (URLs) in 56 of 57 (98%), 37 of 42 ([88%] P=0.03 versus cTnT), and 43 of 57 ([75%] P<0.001 versus cTnT), respectively. This increased rate of positivity for cTnT (93%) versus cTnI ([64%] P<0.001) on admission was confirmed in 87 independent cases from an international registry. In the Franco-German cohort, 24 of 60 (40%) patients developed ≥1 MACE (total, 52; median time to first MACE, 5 [interquartile range, 2-16] days). The highest value of cTnT:URL within the first 72 hours of admission performed best in terms of association with MACE within 90 days (area under the curve, 0.84) than CK:URL (area under the curve, 0.70). A cTnT:URL ≥32 within 72 hours of admission was the best cut-off associated with MACE within 90 days (hazard ratio, 11.1 [95% CI, 3.2-38.0]; P<0.001), after adjustment for age and sex. cTnT was increased in all patients within 72 hours of the first MACE (23 of 23 [100%]), whereas cTnI and CK values were less than the URL in 2 of 19 (11%) and 6 of 22 (27%) of patients (P<0.001), respectively. CONCLUSIONS: cTnT is associated with MACE and is sensitive for diagnosis and surveillance in patients with ICI myocarditis. A cTnT:URL ratio <32 within 72 hours of diagnosis is associated with a subgroup at low risk for MACE. Potential differences in diagnostic and prognostic performances between cTnT and cTnI as a function of the assays used deserve further evaluation in ICI myocarditis.

Increased expression of human endogenous retrovirus K in endomyocardial biopsies from patients with cardiomyopathy - a transcriptomics meta-analysis.

Most studied, investigating transcriptional changes in myocardial biopsies focus on human genes. However, the presence and potential consequence of persistent expression of viral genes within the myocardium is unclear. The aim of the study was to analyze viral gene expression in RNAseq data from endomyocardial biopsies. The NCBI Bioproject library was screened for published projects that included bulk RNA sequencing data from endomyocardial biopsies from both healthy and diseased patients with a sample size greater than 20. Diseased patients with hypertrophic, dilated, and ischemic cardiomyopathies were included. A total of 507 patients with 507 samples from 6 bioprojects were included and mapped to the human genome (hg38). Unmappable sequences were extracted and mapped to an artificial 'super-virus' genome comprising 12,182 curated viral reference genomes. Subsequently, the sequences were reiteratively permutated and mapped again to account for randomness. In total, sequences from 68 distinct viruses were found, all of which were potentially human pathogenic. No increase in cardiotropic viruses was found in patients with dilated cardiomyopathy. However, the expression levels of the particle forming human endogenous retrovirus K were significantly increased (q < 0.0003, ANOVA). Higher expression levels were associated with increased expression in mitochondrial pathways such as oxidative phosphorylation (p < 0.0001). In Conclusion, expression of human endogenous retrovirus K is significantly increased in patients with dilated cardiomyopathy, which in turn was associated with transcriptional alterations in major cellular pathways.

Troponin Elevation in Asymptomatic Cancer Patients: Unveiling Connections and Clinical Implications.

PURPOSE OF THE REVIEW: Elevated troponin levels are well established e.g., for the diagnosis of suspected acute coronary syndrome in symptomatic patients. In contrast, troponin elevations in asymptomatic cancer patients emerge as a complex phenomenon, challenging traditional perceptions of its association solely with cardiac events. RECENT FINDINGS: Recent data support the predictive value of cardiac biomarker for all-cause mortality and cardiotoxicity in cancer patients. This review gives an overview about the current literature about cardiac troponins in prediction and identification of high-risk cancer patients. The overview is focusing on diagnostic challenges, biomarker significance, and gaps of knowledge. Latest publications highlight the relevance of cardiac troponin in risk analysis before cancer treatment as well as a potential diagnostic gatekeeper for further cardiological diagnostics and therapy.

Travel Distance and Spanish-Speaking are Associated with Delays in the Treatment of Cleft Palate.

OBJECTIVE: Delayed repair of cleft palate is associated with worse speech outcomes. Social determinants of health may influence the timing of surgery; however, there are no population health investigations to evaluate factors such as travel distance, language barriers, and payer. This study sought to identify factors that may interfere with timely cleft palate repair. DESIGN: Retrospective cohort. SETTING: National/multi-center. PATIENTS/PARTICIPANTS: All cleft palate repairs within California were extracted from 2000-2021. MAIN OUTCOMES MEASURES: The primary outcome was age at surgical repair, which was modeled with linear regression. Covariates included race, primary language, distance from patient home to hospital, socioeconomic status, primary payer, and managed care enrollment status. RESULTS: 11 260 patients underwent surgical repair of a cleft palate. Black race was associated with delayed repair (22 additional days, P = .004, 95% CI 67.00-37.7) along with Asian/Pacific-Islander race (11 additional days, P = .006, 95% CI 3.26-18.9) compared to white race. Spanish-speaking patients had significantly later cleft palate repairs by 19 days, (P < .001, 95% CI 10.8-27.7) compared with English-speaking. Further distances from the hospital were significantly associated with later cleft surgeries with out-of-state patients undergoing surgery 52 days later (P < .001, 95% CI 11.3-24.3). Managed care plans and Medi-Cal were significantly associated with earlier surgical repair compared with private insurance. CONCLUSION: Black, Asian Pacific Islander, and Spanish-speaking patients and greater distance traveled to hospital were associated with delayed cleft palate repairs. These results underscore the importance of addressing structural and social barriers to care to improve outcomes and reduce health disparities for patients with cleft palate.

Effect of SARS-CoV-2 mRNA-Vaccine on the Induction of Myocarditis in Different Murine Animal Models.

In the course of the SARS-CoV-2 pandemic, vaccination safety and risk factors of SARS-CoV-2 mRNA-vaccines were under consideration after case reports of vaccine-related side effects, such as myocarditis, which were mostly described in young men. However, there is almost no data on the risk and safety of vaccination, especially in patients who are already diagnosed with acute/chronic (autoimmune) myocarditis from other causes, such as viral infections, or as a side effect of medication and treatment. Thus, the risk and safety of these vaccines, in combination with other therapies that could induce myocarditis (e.g., immune checkpoint inhibitor (ICI) therapy), are still poorly assessable. Therefore, vaccine safety, with respect to worsening myocardial inflammation and myocardial function, was studied in an animal model of experimentally induced autoimmune myocarditis. Furthermore, it is known that ICI treatment (e.g., antibodies (abs) against PD-1, PD-L1, and CTLA-4, or a combination of those) plays an important role in the treatment of oncological patients. However, it is also known that treatment with ICIs can induce severe, life-threatening myocarditis in some patients. Genetically different A/J (most susceptible strain) and C57BL/6 (resistant strain) mice, with diverse susceptibilities for induction of experimental autoimmune myocarditis (EAM) at various age and gender, were vaccinated twice with SARS-CoV-2 mRNA-vaccine. In an additional A/J group, an autoimmune myocarditis was induced. In regard to ICIs, we tested the safety of SARS-CoV-2 vaccination in PD-1-/- mice alone, and in combination with CTLA-4 abs. Our results showed no adverse effects related to inflammation and heart function after mRNA-vaccination, independent of age, gender, and in different mouse strains susceptible for induction of experimental myocarditis. Moreover, there was no worsening effect on inflammation and cardiac function when EAM in susceptible mice was induced. However, in the experiments with vaccination and ICI treatment, we observed, in some mice, low elevation of cardiac troponins in sera, and low scores of myocardial inflammation. In sum, mRNA-vaccines are safe in a model of experimentally induced autoimmune myocarditis, but patients undergoing ICI therapy should be closely monitored when vaccinated.

Cardio-oncology imaging tools at the translational interface.

Cardiovascular imaging is an evolving component in the care of cancer patients. With improved survival following prompt cancer treatment, patients are facing increased risks of cardiovascular complications. While currently established imaging modalities are providing useful structural mechanical information, they continue to develop towards increased specificity. New modalities, emerging from basic science and oncology, are being translated, targeting earlier stages of cardiovascular disease. Besides these technical advances, matching an imaging modality with the patients' individual risk level for a specific pathological change is part of a successful imaging strategy. The choice of suitable imaging modalities and time points for specific patients will impact the cardio-oncological risk stratification during surveillance and follow-up monitoring. In addition, future imaging tools are poised to give us important insights into the underlying cardiovascular molecular pathology associated with cancer and oncological therapies. This review aims at giving an overview of the novel imaging technologies that have the potential to change cardio-oncological science and clinical practice in the near future.

Histone deacetylase 4 deletion broadly affects cardiac epigenetic repression and regulates transcriptional susceptibility via H3K9 methylation.

Histone deacetylase 4 (HDAC4) is a member of class IIa histone deacetylases (class IIa HDACs) and is believed to possess a low intrinsic deacetylase activity. However, HDAC4 sufficiently represses distinct transcription factors (TFs) such as the myocyte enhancer factor 2 (MEF2). Transcriptional repression by HDAC4 has been suggested to be mediated by the recruitment of other chromatin-modifying enzymes, such as methyltransferases or class I histone deacetylases. However, this concept has not been investigated by an unbiased approach. Therefore, we studied the histone modifications H3K4me3, H3K9ac, H3K27ac, H3K9me2 and H3K27me3 in a genome-wide approach using HDAC4-deficient cardiomyocytes. We identified a general epigenetic shift from a 'repressive' to an 'active' status, characterized by an increase of H3K4me3, H3K9ac and H3K27ac and a decrease of H3K9me2 and H3K27me3. In HDAC4-deficient cardiomyocytes, MEF2 binding sites were considerably overrepresented in upregulated promoter regions of H3K9ac and H3K4me3. For example, we identified the promoter of Adprhl1 as a new genomic target of HDAC4 and MEF2. Overexpression of HDAC4 in cardiomyocytes was able to repress the transcription of the Adprhl1 promoter in the presence of the methyltransferase SUV39H1. On a genome-wide level, the decrease of H3K9 methylation did not change baseline expression but was associated with exercise-induced gene expression. We conclude that HDAC4, on the one hand, associates with activating histone modifications, such as H3K4me3 and H3K9ac. A functional consequence, on the other hand, requires an indirect regulation of H3K9me2. H3K9 hypomethylation in HDAC4 target genes ('first hit') plus a 'second hit' (e.g., exercise) determines the transcriptional response.

Reduced bone mineral density in adolescents with Duchenne Muscular Dystrophy (DMD) and scoliosis.

Duchenne muscular dystrophy is a progressive disease usually associated with loss of ambulation and progressive scoliosis. Immobilisation and glucocorticoid treatment are predisposing factors for reduced bone mineral density (BMD). Analysis of quantitative computed tomography revealed low BMD in thoracic and lumbar vertebrae in comparison to age- and sex-matched healthy controls. INTRODUCTION: Evaluation of vertebral bone mineral density (BMD) in Duchenne Muscular Dystrophy (DMD) adolescents with untreated advanced scoliosis and comparison with the BMD values of healthy age-matched controls, based on quantitative computer tomography. METHODS: Thirty-seven DMD adolescents (age 15.6 ± 2.5 years) with spinal deformity were evaluated clinically and radiologically prior to definite spinal fusion and compared to 31 male and age-matched healthy individuals (age 15.7 ± 2.3 years). Data related to previous medical treatment, physiotherapy and ambulatory status was also analysed. Scoliotic curves were measured on plain sitting radiographs of the spine. The BMD Z-scores of the thoracic and lumbar vertebrae were calculated with QCTpro® (Mindways Software Inc., USA), based on data sets of preoperative, phantom pre-calibrated spinal computed tomography scans. RESULTS: A statistically significant lower BMD could be found in DMD adolescents, when compared to healthy controls, showing an average value for the lumbar spine of 80.5 ± 30.5 mg/cm3. Z-scores deteriorated from the upper thoracic towards the lower lumbar vertebrae. All but the uppermost thoracic vertebrae had reduced BMD values, with the thoracolumbar and lumbar region demonstrating the lowest BMD. No significant correlation was observed between BMD and the severity of the scoliotic curve, previous glucocorticoid treatment, cardiovascular impairment, vitamin D supplementation, non-invasive ventilation or physiotherapy. CONCLUSION: DMD adolescents with scoliosis have strongly reduced BMD Z-scores, especially in the lumbar spine in comparison to healthy controls. These findings support the implementation of a standardised screening and treatment protocol. Level of evidence/clinical relevance: therapeutic level III.

Enhanced recovery after cleft palate repair: A quality improvement project.

BACKGROUND: Children undergoing cleft palate repair present challenges to postoperative management due to several factors that can complicate recovery. Utilization of multimodal analgesic protocols can improve outcomes in this population. We report experience designing and implementing an enhanced recovery after surgery (ERAS) pathway for cleft palate repair to optimize postoperative recovery. AIMS: The primary aim was to implement an ERAS pathway with >70% bundle adherence to achieve a 30% reduction in postoperative opioid consumption within 12 months. Our secondary aims assessed intraoperative opioid consumption, length of stay, timeliness of oral intake, and respiratory recovery. METHODS: A multidisciplinary team of perioperative providers developed an ERAS pathway for cleft palate patients. Key drivers included patient and provider education, formal pathway creation and implementation, multimodal pain therapy, and target-based care. Interventions included maxillary nerve blockade and enhanced intra- and postoperative medication regimens. Outcomes were displayed as statistical process control charts. RESULTS: Pathway compliance was 77.0%. Patients during the intervention period (n = 39) experienced a 49% reduction in postoperative opioid consumption (p < .0001) relative to our historical cohort (n = 63), with a mean difference of -0.33 ± 0.11 mg/kg (95% CI -0.55 to -0.12 mg/kg). Intraoperative opioid consumption was reduced by 36% (p = .002), with a mean difference of -0.27 ± 0.09 mg/kg (95% CI -0.45 to -0.09 mg/kg). Additionally, patients in the intervention group had a 45% reduction in time to first oral intake (p = .02) relative to our historical cohort, with a mean difference of -3.81 ± 1.56 h (95% CI -6.9 to -0.70). There was no difference in PACU or hospital length of stay, but there was a significant reduction in variance of all secondary outcomes. CONCLUSION: Opioid reduction and improved timeliness of oral intake is possible with an ERAS protocol for cleft palate repair, but our protocol did not alter PACU or hospital length of stay.

CaM kinase II regulates cardiac hemoglobin expression through histone phosphorylation upon sympathetic activation.

Sympathetic activation of ß-adrenoreceptors (ß-AR) represents a hallmark in the development of heart failure (HF). However, little is known about the underlying mechanisms of gene regulation. In human ventricular myocardium from patients with end-stage HF, we found high levels of phosphorylated histone 3 at serine-28 (H3S28p). H3S28p was increased by inhibition of the catecholamine-sensitive protein phosphatase 1 and decreased by ß-blocker pretreatment. By a series of in vitro and in vivo experiments, we show that the ß-AR downstream protein kinase CaM kinase II (CaMKII) directly binds and phosphorylates H3S28. Whereas, in CaMKII-deficient myocytes, acute catecholaminergic stimulation resulted in some degree of H3S28p, sustained catecholaminergic stimulation almost entirely failed to induce H3S28p. Genome-wide analysis of CaMKII-mediated H3S28p in response to chronic ß-AR stress by chromatin immunoprecipitation followed by massive genomic sequencing led to the identification of CaMKII-dependent H3S28p target genes. Forty percent of differentially H3S28p-enriched genomic regions were associated with differential, mostly increased expression of the nearest genes, pointing to CaMKII-dependent H3S28p as an activating histone mark. Remarkably, the adult hemoglobin genes showed an H3S28p enrichment close to their transcriptional start or end sites, which was associated with increased messenger RNA and protein expression. In summary, we demonstrate that chronic ß-AR activation leads to CaMKII-mediated H3S28p in cardiomyocytes. Thus, H3S28p-dependent changes may play an unexpected role for cardiac hemoglobin regulation in the context of sympathetic activation. These data also imply that CaMKII may be a yet unrecognized stress-responsive regulator of hematopoesis.

Out-of-Pocket Costs and Provider Payments in Cleft Lip and Palate Repair.

BACKGROUND: As healthcare spending within the United States grows, payers have attempted to curb spending through higher cost sharing for patients. For families attempting to balance financial obligations with their children's surgical needs, high cost sharing could place families in difficult situations, deciding between life-altering surgery and bankruptcy. We aim to investigate trends in patient cost sharing and provider payments for cleft lip and palate repair. METHODS: The IBM® MarketScan® Commercial Database was queried to extract patients younger than 18 years who underwent primary or secondary cleft lip and/or palate repair from 2007 to 2016. Financial variables included gross payments to the provider (facility and/or physician), net payment as reported by the carrier, coordination of benefits and other savings, and the beneficiary contribution, which consisted of patients' coinsurance, copay, and deductible payments. Linear regression was used to evaluate trends in payments over time. Poisson regression was used to trend the proportion of patients with a nonzero beneficiary contribution. All financial values were adjusted to 2016 dollars per the consumer price index to account for inflation. RESULTS: The sample included 6268 cleft lip and 9118 cleft palate repair episodes. Total provider payments increased significantly from 2007 to 2016 for patients undergoing cleft lip (median, $2527.33 vs $5116.30, P 0.008) and palate ($1766.13 vs $3511.70, P < 0.001) repair. Beneficiary contribution also increased significantly for both cleft lip ($155.75 vs $193.31, P < 0.001) and palate ($124.37 vs $183.22, P < 0.001) repair, driven by an increase in deductibles ( P < 0.002). The proportion of cleft palate patients with a nonzero beneficiary contribution increased yearly by 1.6% ( P = 0.002). Higher provider payments and beneficiary contributions were found in the Northeast ( P < 0.001) and South ( P < 0.011), respectively, for both cleft lip and palate repair. CONCLUSIONS: The US national data demonstrate that for commercially insured patients with cleft lip and/or palate, there has been a trend toward higher patient cost sharing, most pronounced in the South. This suggests that patients are bearing an increased cost burden while provider payments are simultaneously accelerating. Additional studies are needed to understand the impact of increased cost sharing on parents' decision to pursue cleft lip and/or palate repair for their children.

A Systematic Review of Mandibular Distraction Osteogenesis Versus Orthodontic Airway Plate for Airway Obstruction Treatment in Pierre Robin Sequence.

OBJECTIVE: Mandibular distraction osteogenesis (MDO) is frequently performed to address airway obstruction in patients with Pierre Robin sequence (PRS), though more recently the technique of orthodontic airway plating (OAP) has gained traction. We aimed to evaluate OAP compared to MDO for airway obstruction in PRS. DESIGN: A systematic literature search across PubMed, Embase, and Google Scholar identified all studies published in English, which involved MDO or any form of OAP as treatments for PRS. All relevant articles were reviewed in detail and reported on, adhering to PRISMA guidelines. MAIN OUTCOME MEASURES: Airway (tracheostomy avoidance, decannulation rate), feeding (full oral feeding tolerance). RESULTS: Literature search identified 970 articles, of which 42 MDO studies and 9 OAP studies met criteria for review. A total of 1159 individuals were treated with MDO, and 322 individuals were treated with OAP. Primary outcomes appear similar for MDO and OAP at face value; however, this must be interpreted with different pretreatment contexts in mind. CONCLUSIONS: Orthodontic airway plating may be considered for airway obstruction in PRS, as some airway-related and feeding-related outcomes appear similar with MDO, per existing evidence in the literature. However, since PRS severity differed between studies, OAP cannot be uniformly considered a replacement for MDO. Further research is required to more comprehensively assess these treatment modalities inclusive of metrics that allow for direct comparison.

[Further development of regional early care-Many roads lead to Rome : Developmental stages of four established rheumatological early care concepts in different regions of Germany]. / Regionale Frühversorgung weiterentwickeln ­ Viele Wege führen nach Rom : Entwicklungsetappen von 4 etablierten rheumatologischen Frühversorgungskonzepten in verschiedenen Regionen Deutschlands.

In order to shorten the prognostically relevant waiting time until diagnosis and initiation of appropriate treatment in inflammatory rheumatic diseases, rheumatological centers in many regions across Germany have established and continuously developed specific early care concepts. Evaluated models from Altötting·Burghausen, Berlin Buch, Düsseldorf and Heidelberg and their developmental stages as a response to internal and external challenges are presented in this overview. The transparent publication of the developmental steps and the exchange of experiences aim at promoting new early care concepts in other regions and continuing the joint dialogue for improvement of the early detection and quality of care of inflammatory rheumatic diseases in Germany.

[Development of quality standards for patients with rheumatoid arthritis for use in Germany]. / Entwicklung von Qualitätsstandards für die Versorgung von Patient*innen mit rheumatoider Arthritis zur Anwendung in Deutschland.

Despite a qualitatively and structurally good care of patients with rheumatoid arthritis (RA) in Germany, there are still potentially amendable deficits in the quality of care. For this reason, the German Society for Rheumatology (DGRh) has therefore decided to ask a group of experts including various stakeholders to develop quality standards (QS) for the care of patients with RA in order to improve the quality of care. The QS are used to determine and quantitatively measure the quality of care, subject to relevance and feasibility. The recently published NICE and ASAS standards and a systematic literature search were used as the basis for development. A total of 8 QS, now published for the first time, were approved with the intention to measure and further optimize the quality of care for patients with RA in Germany.

[Development of quality standards for patients with axial spondyloarthritis for use in Germany]. / Entwicklung von Qualitätsstandards für Patient*innen mit axialer Spondyloarthritis zum Einsatz in Deutschland.

Quality standards (QS) are measurable constructs designed to quantify gaps in care and subsequently to improve quality of care. The Assessment of SpondyloArthritis International Society (ASAS) recently generated and published international QS for the management of patients with axial spondyloarthritis (axSpA) for the first time. The German Society of Rheumatology (DGRh) then decided to translate, review and possibly adopt these standards by a group of experts from different care settings. Against this background, national QS for the management of patients with axSpA for Germany were developed for the first time. The main focus was on feasibility and practical relevance. Ultimately, nine QS were defined with which the quality of care in Germany can and should be measured and improved.

Wounds Inhibit Tumor Growth In Vivo.

OBJECTIVE: The aim of this study was to determine the interaction of full thickness excisional wounds and tumors in vivo. SUMMARY OF BACKGROUND DATA: Tumors have been described as wounds that do not heal due to similarities in stromal composition. On the basis of observations of slowed tumor growth after ulceration, we hypothesized that full thickness excisional wounds would inhibit tumor progression in vivo. METHODS: To determine the interaction of tumors and wounds, we developed a tumor xenograft/allograft (human head and neck squamous cell carcinoma SAS/mouse breast carcinoma 4T1) wound mouse model. We examined tumor growth with varying temporospatial placement of tumors and wounds or ischemic flap. In addition, we developed a tumor/wound parabiosis model to understand the ability of tumors and wounds to recruit circulating progenitor cells. RESULTS: Tumor growth inhibition by full thickness excisional wounds was dose-dependent, maintained by sequential wounding, and relative to distance. This effect was recapitulated by placement of an ischemic flap directly adjacent to a xenograft tumor. Using a parabiosis model, we demonstrated that a healing wound was able to recruit significantly more circulating progenitor cells than a growing tumor. Tumor inhibition by wound was unaffected by presence of an immune response in an immunocompetent model using a mammary carcinoma. Utilizing functional proteomics, we identified 100 proteins differentially expressed in tumors and wounds. CONCLUSION: Full thickness excisional wounds have the ability to inhibit tumor growth in vivo. Further research may provide an exact mechanism for this remarkable finding and new advances in wound healing and tumor biology.

Epigenetic regulation of cardiac electrophysiology in atrial fibrillation: HDAC2 determines action potential duration and suppresses NRSF in cardiomyocytes.

Atrial fibrillation (AF) is associated with electrical remodeling, leading to cellular electrophysiological dysfunction and arrhythmia perpetuation. Emerging evidence suggests a key role for epigenetic mechanisms in the regulation of ion channel expression. Histone deacetylases (HDACs) control gene expression through deacetylation of histone proteins. We hypothesized that class I HDACs in complex with neuron-restrictive silencer factor (NRSF) determine atrial K+ channel expression. AF was characterized by reduced atrial HDAC2 mRNA levels and upregulation of NRSF in humans and in a pig model, with regional differences between right and left atrium. In vitro studies revealed inverse regulation of Hdac2 and Nrsf in HL-1 atrial myocytes. A direct association of HDAC2 with active regulatory elements of cardiac K+ channels was revealed by chromatin immunoprecipitation. Specific knock-down of Hdac2 and Nrsf induced alterations of K+ channel expression. Hdac2 knock-down resulted in prolongation of action potential duration (APD) in neonatal rat cardiomyocytes, whereas inactivation of Nrsf induced APD shortening. Potential AF-related triggers were recapitulated by experimental tachypacing and mechanical stretch, respectively, and exerted differential effects on the expression of class I HDACs and K+ channels in cardiomyocytes. In conclusion, HDAC2 and NRSF contribute to AF-associated remodeling of APD and K+ channel expression in cardiomyocytes via direct interaction with regulatory chromatin regions. Specific modulation of these factors may provide a starting point for the development of more individualized treatment options for atrial fibrillation.

[Future of acute inpatient rheumatology in Germany : Statement of the Boards of the German Society for Rheumatology and the Association of Rheumatological Acute Clinics on hospital planning North-Rhine/Westphalia 2019 for the discipline rheumatology]. / Zukunft der akutstationären Rheumatologie in Deutschland : Stellungnahme der DGRh- und VRA-Vorstände zur Krankenhausplanung NRW 2019 für den Leistungsbereich Rheumatologie.

In September 2019 the Ministry of Labor, Health and Welfare (MAGS) of North-Rhine/Westphalia (NRW) published an expert report on hospital planning. In this report a fundamental reform of hospital planning was recommended, in that a requirements planning should be carried out in the future on the basis of a detailed designation of disciplines and organizational groups. At the request of the MAGS NRW, the German Society for Rheumatology (DGRh) with the support of the Association of Rheumatological Acute Clinics (VRA) has also commented on this issue.

[Rheumatology in German MD curricula]. / Rheumatologie im Medizinstudium.

Transmitting a substantial amount of basic knowledge in Rheumatology to all medical students is essential for the future medical care of patients with rheumatic diseases for two reasons: on the one hand, future general practitioners will need to master the patterns of rheumatic diseases to recognize them fast enough in new-onset patients and to refer them in time and directly to rheumatologists. On the other hand, the shortage of rheumatologists can only then be relieved in the future when we are able to inspire enthusiasm for our specialty. Adequate rheumatological structures are established only in some of the German faculties of medicine. Structural improvements happen in small steps only but were achieved at several sites. The better the local structures, the higher the chances of committed university teachers in rheumatology to reach all medical students. Probably from 2026 onwards, the learning objectives relevant for examinations will be defined by the national competence-based catalogue of learning objectives in medicine (NKLM), which is currently in the final stages of completion together with the German Federal Institute for Medical and Pharmaceutical Examinations (IMPP). It now appears that systemic autoimmune diseases and inflammatory rheumatic diseases are adequately depicted in this catalogue. If this is achieved, students will know more about these diseases in the future and will diagnose them faster in patients. Work on the NKLM is therefore of highest importance. In addition to the work on the learning objectives, up to date learning materials are required, which have to be available throughout Germany. A Rheumatology script just finished by the committee for medical student education of the German Society of Rheumatology (DGRh) and now available on the DGRh homepage should close this gap.

Mission statement from rheumatologists in the German Society of Rheumatology (DGRh e. V.) : We live rheumatology.

Systemic disease demands systemic thinkers. In this mission statement we define rheumatology, describe the role of the German Society of Rheumatology and the rheumatologist's spirit to their discipline. Rheumatologists are dedicated to improving the quality of life of their acute, chronic, and rehabilitative patients on the basis of up to date evidence and strong physician-patient relations. We think, act and interact systemically, scientifically, consistently, transparently, reliably, inclusively, innovatively and enthusiastically.